Compositions containing dolichol for dermatological and cosmetic use

ABSTRACT

Disclosed are cosmetic and dermatological compositions containing dolichol which are active against the harmful action of light and free radicals, and against skin aging.

The present invention relates to cosmetic and dermatologicalcompositions containing dolichol, and in particular to compositionswhich prevent the harmful action of light, free radicals and oxygen andskin aging, and are also useful to regularise skin pigmentation andsebum secretion. This activity is performed by enhancing the skinnatural defences.

INTRODUCTION

The skin consists of a set of cells whose state is reflected by theexternal appearance of the epidermis. It is continually exposed to theharmful effects of reactive substances (free radicals), which may beendogenous (products of skin cell metabolism) or originate from theoutside world (high oxygen concentrations; radical generators present inthe environment, including smoke, sunlight, etc.) and are responsiblefor harmful acute and chronic symptoms, and in particular for intrinsicand extrinsic skin aging, respectively. The skin aging process is causedby a reduction in the functions of the dermis and the epidermis,especially nutrition, respiration, moisturisation, regeneration andprotection of the skin tissues. Skin aging is a natural phenomenon; itscauses are variable, and the speed with which it takes place varies fromperson to person, depending partly on the defences of the skin and thefunction of the adnexal glands, especially the sebaceous glands, whichdeposit protective materials on the skin surface. A slowing in thefunctions of some cells which play a very important part in maintainingthe integrity of the epidermal structure generally begins to appear ataround the age of 30, but is due to a number of factors, such as geneticbackground, general state of health, lifestyle and environment (A.Chuttani and B. A. Gilchrest in E. Masoro (ed). Handbook of PhysiologySection 11: Aging. 1995, pp.309-324).

Particular concern has been aroused by the change in composition of thesunlight spectrum that reaches the earth surface due to the thinning ofthe ozone layer. This has led to an increase in the proportion ofultraviolet radiation reaching the earth surface, namely UVA (320-400nm), UVB (290-320 nm) and UVC (200-290 nm), which once constituted 3-5%of solar radiation energy but are now increasing so much that there hasbeen a significant rise in the frequency of malignant skin tumours.Carcinogenic action is mainly attributable to UVB rays, which act ascomplete carcinogens, ie. have both an initiating and a promotingaction. The tumours caused by UV rays include basal cell and squamouscell carcinomas, and probably also the far more serious melanomas.Excessive exposure to sunlight in the first few years of life isbelieved to constitute a particular risk for the appearance of melanoma.

Photoprotection measures, including application to exposed surfaces ofsunscreens, namely substances able to absorb or block UVA and UVBradiation to varying extents, are increasingly recommended to preventthe damage caused by over-exposure to UV rays (reduction in the skinimmune defences, alterations in skin pigmentation, premature aging andalterations in dermal capillaries). There are two main types ofsunscreen: chemical and physical. Chemical sunscreens are chromophoresable to absorb energy in the UVB and UVA regions, thus reducing thenumber of photons that penetrate the skin. The main categories ofchemical sunscreens currently used are para-aminobenzoic acid and itsesters; benzophenones, anthranylates, cinnamates and salicylates.Physical sunscreens are mixtures opaque to light, based on zinc oxide,talc and titanium oxide, with good reflecting power. In addition to thelight absorption or reflection characteristics of the product, theefficacy of sunscreens depends on a number of factors, including theamount of product intentionally applied (the most important factor) andthe distribution procedures (Diffey B L, Sunscreens and UVA protection:a major issue of minor importance. Photochem Photobiol 2001 July;74(1):61-3).

All currently known sunscreens present drawbacks which can make theiruse harmful, especially over the long term. One drawback is diacutaneousabsorption of the constituents of the preparation, with harmfulconsequences in the skin or at systemic level.

Recent studies have given rise to new concern about the consequences ofthe increasing dissemination in the environment of many synthetic UVfilters which are not easily biodegradable. Among them, some widely usedsubstances (benzophenone-3 (Bp-3), homosalate (HMS),4-methyl-benzylidene camphor (4-MBC), octyl-methoxycinnamate (OMC) andoctyl-dimethyl-PABA (OD-PABA) have oestrogenic effects, which can bedangerous because of their bioaccumulation capacity in a wide variety ofliving species (Schlumpf M, Cotton B, Conscience M, Haller V, SteinmannB, Lichtensteiger W. In vitro and in vivo estrogenicity of UV screens.Environ Health Perspect 2001 March; 109(3):239-44).

All these drawbacks can be overcome by using natural antioxidants. Ifadministered orally, they reach the skin through the bloodstream, andcan also reach the surface of the epidermis if they are excreted withthe sebum. Sebum continually deposits antioxidant substances such asVitamin E on the skin surface. Applications of Vitamin E to the skinsurface have a significant photoprotective effect, but it isshort-lived, because alpha-tocopherol is rapidly consumed byphoto-oxidation and polymerisation (Krol E S, Kramer-Stickland K A,Liebler D C. Photoprotective actions of topically applied vitamin E.Drug Metab Rev 2000 August-November; 32(3-4):413-20). Other naturalantioxidant substances currently being studied are carotenes andpolyunsaturated fatty acids (Glaser D A, Rogers C. Topical and systemictherapies for the aging face. Facial Plast Surg Clin North Am 2001 May;9(2):189-96). Drinking infusions of green tea, and above all localapplication of extracts containing the polyphenol components(−)-epigallocatechin-3-gallate (EGCG) and (−)-epicatechin-3-gallate(ECG) have also proved effective (Ahmad N, Mukhtar H., Cutaneousphotochemoprotection by green tea: a brief review. Skin Pharmacol ApplSkin Physiol 2001 March-April; 14(2):69-76; Elmets C A, Singh D,Tubesing K, Matsui M, Katiyar S, Mukhtar H. Cutaneous photoprotectionfrom ultraviolet injury by green tea polyphenols. J Am Acad Dermatol2001 March; 44(3):425-32).

U.S. Pat. No. 6,261,575 discloses dermatological preparations whichcontain sterols and their biochemical precursors in combination withubiquinones and/or plastoquinones. Various substances, such assubstances with an aerobic cellular energy metabolism, can be added tothese formulations; such substances surprisingly include dolichol, aproduct of the mevalonate metabolic pathway, high concentrations ofwhich are present in human sebum (0.2 mg/g of fresh weight).

DESCRIPTION OF THE INVENTION

It has now been found that dolichol as is possesses antioxidantproperties and can be used as a sunscreen to prevent acute or chronicdamage caused by exposure to sunlight.

The present invention relates to cosmetic and dermatologicalcompositions containing dolichol for the prevention of acute and chronicskin damage caused by exposure to sunlight. Dolichol is used at aconcentration of between 0.001 and 7% by weight, preferably between 0.02and 5% by weight, and may be associated with other fat-soluble vitaminicactive ingredients with an anti-radical action such as Vitamin E andVitamin F, which stabilise it and prolong its effects over time, and/orwith plant polyprenoids from which dolichol can be synthesised.

The compositions of the invention are prepared according to techniquesand with excipients known in dermatology and cosmetics, such as thosedescribed in Remington's Pharmaceutical Handbook, 17th ed., Mack Pub.,N.Y., U.S.A., and may be presented in the form of creams, lotions,milks, fatty ointments, oils, ampoules, sticks and sprays, the solelimitation being the solubility characteristics of dolichol. Thepreferred propellant for the spray is carbon dioxide.

Dermatological and cosmetic compositions in paraffin and oils, which arewell tolerated and do not cause irritation due to the active constituentor its interactions with the vehicle, even at the highest dolicholconcentrations, are particularly preferred.

The invention will be illustrated below by means of the followingexamples.

EXAMPLES

In examples 1-5, the amounts are expressed in grams.

Example 1 Cream

Dehymuls F ® 9 Oleyl eructate 6 Decyl oleate 6 Isooctyl stearate 5 Whitevaseline 10 Dolichol 0.2 Glycerin 3 Magnesium sulphate 0.3 Water 60.5100

Example 2 Cream

Dehymuls K ® 8 Triglycerides of caprylic acid and lauric 4 acid Decyloleate 6 Vegetable oil 6 White vaseline 9 Paraffin oil 6 Dolichol 0.5Glycerin 3 Vitamin E 0.5 Vitamin F 0.5 Magnesium sulphate 0.3 Water 56.2100

Example 3 Cream

Glyceryl monostearate 16 Cetyl alcohol 1 Mineral oil 10 Sesame oil 9Glycerin 7 Vitamin E 1 Dolichol 1 Water 55 100

Example 4 Liquid Emulsion

Cutin MD ® 7 Cetyl stearyl alcohol 3 Cetiol SN ® 11 Triglycerides ofcaprylic acid and capric 11 acid Dolichol 0.1 Water 67.9 100

Example 5 Spray Solution

Octyl dodecanol 55 Vegetable oil 20 Paraffin oil 23 Dolichol 2 100

The solution is mixed with carbon dioxide to give a 50:50 mixture.

Example 6 Study of Anti UV-B Activity

After irradiation, dolichol undergoes transformations in the mostdangerous spectral region (UVB), depending on the dose of radiationapplied; it absorbs UV radiation and, if irradiated with UVC rays,instantly acquires an absorption capacity in the UVB region. Thisphenomenon leads to a very rapid increase in absorbance at 320 nm (up430% in one minute; up 580% in two minutes), with more modest increasesin absorbance at 250 nm. The phenomenon is very weak in the case ofirradiation with monochromatic light at 310 nm, more intense withirradiation at 280 nm, and greatest with white light irradiation, namelywith the entire emission spectrum of the xenon lamp. It has beendemonstrated that due to the effect of UV photo-irradiation in an oxygenatmosphere, the dolichol molecules undergo an apparent breakdown,accompanied by disappearance of UVC absorption capacity and therefore byconsumption of the substance. The photodecomposition products ofdolichol have not yet been identified but, by analogy with the findingsmade with peroxidative degradation of dolichol in isolated hepatocytestreated with carbon tetrachloride, it can be concluded that inbiological systems, the degradation cascade leads to the formation ofthiobarbituric acid reactive substances (TBARS), which are readilymetabolised and detoxified by the body in the event of resorption. Onthe basis of theoretical knowledge, strengthened by the demonstrationthat the degradation of dolichol and the formation of TBARS inhepatocytes treated with CCl₄ is prevented by administering Vitamin E,the existence of some interesting positive interactions between thephotoprotective effects of dolichol and those of Vitamin E can bepostulated. The release by dolichol of biologically active substances,according to the extent of the photo-irradiation, suggests that it playsa complex role in controlling the natural adaptation mechanisms of theskin and its defences against the effects of sunlight. As regardsabsorption, it should be borne in mind that dolichol is a normalconstituent of all cell membranes, in which it is synthesised andremains until breakdown, without being resorbed into the bloodstream orbeing transferable to other tissues.

In vivo photoprotection tests using dolichol (approx. 1 mg/cm2)demonstrate that the substance does not have cell-damaging effects or(photo)sensitising effects.

1. Cosmetic and dermatological compositions containing dolichol mixedwith suitable excipients and/or additives.
 2. Compositions as claimed inclaim 1, wherein the dolichol concentration is between 0.001 and 7% byweight.
 3. Compositions as claimed in claim 1, wherein the dolicholconcentration is between 0.002 and 5% by weight.
 4. Compositions asclaimed in claim 1, wherein dolichol is associated with otherfat-soluble vitaminic active ingredients possessing an anti-radicalaction and/or with plant polyprenoids.
 5. Compositions as claimed inclaim 4, wherein the fat-soluble vitaminic active ingredients with ananti-radical action are Vitamin E and Vitamin F and/or plantpolyprenoids.
 6. Compositions as claimed in claim 1, in the form ofcreams, lotions, milks, ointments, oils, ampoules, sticks and sprays. 7.Compositions as claimed in claim 6, in spray form.
 8. Compositions asclaimed in claim 7, wherein the propellant is carbon dioxide.
 9. The useof dolichol for the preparation of cosmetic and dermatologicalcompositions designed to prevent acute and chronic skin damage caused byexposure to sunlight.